The immune system protects the body against infectious agents, including bacteria, viruses, fungi, and parasites. In addition, the immune system protects against cancer, as well as disease states that result from immune imbalance, opportunistic infections, and autoimmune disorders (Penney, U.S. Pat. No. 5,980,913). Stimulation of the immune system by pharmaceuticals is an important approach to the prevention and treatment of agents that cause immune suppressed states.
The response by the immune system to an immunogen may be depressed as a consequence of certain diseases or pathological conditions. For example, patients infected with the human immunodeficiency virus (HIV-1) may develop acquired immune deficiency syndrome (AIDS) or AIDS related complex (ARC), and thus have depressed immune responses. This patient class is more susceptible to pathological infections or malignancies against which a normal immune system would have otherwise provided sufficient protection. Other such immunocompromised individuals include patients with cancer, or undergoing x-ray, surgery, or chemotherapy treatment.
Current treatments used to prevent the development of immunodeficiency in individuals with viral infections, HIV for example, usually involve administration of compounds that inhibit viral DNA synthesis thereby slowing onset of viral-related immunosuppression. Treatments for HIV-infected patients often involves administration of compounds such as, for example, 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxycytidine (DDC) and 2′,3′-dideoxyinosine (DDI), zidovudine, didanosine, zalcitabine, stavudine, and viramune. More recent treatments against HIV include administration of protease inhibitors such as, for example, saquinovir, nefinavir, ritonavir, indinavir, and others. Cytokine therapy is also used in the treatment of AIDS patients, with research groups having demonstrated efficacy of interleukin-2 (IL2) in elevating the CD4 T-cell subset in HIV positive patients (Kovacs, et al., N. Engl. J. Med., 1996; 335: 1350-1356). Reports have detailed that IL2 can also increase CD8 T-cell count (Schmitz, et al., Science, 1999; 283: 857-860). Unfortunately, the use of IL2 is normally accompanied by major toxicity (Davey, et al., JAMA, 2000; 284: 183-189). Nevertheless, given the potential promise of these therapies directed toward anti-retroviral effects, none have proven to be totally effective in treating or preventing development of AIDS. In addition, many of these compounds cause adverse side effects including low platelet count, diarrhea, nausea, renal toxicity, and bone marrow cytopenia (Kempf, et al., U.S. Pat. No. 6,017,928; Lai, et al., U.S. Pat. No. 6,093,743). Numerous clinical studies with methionine enkephalin (met-enkephalin) in normal volunteers, HIV positive, and cancer patients showed no major toxicity (Plotnikoff, et al, Clin. Immun. Immunopath., 1997). However, the measured half-life of met-enkephalin in plasma is approximately 2 minutes (Bihari, et al., Seventh Int. Conf. On AIDS, 1991). Thus, there exists a need in the art for improved methods of stimulating a sustained immune system response in patients in need of such treatment, such as patients include those with compromised immune system responses (e.g. AIDS), or the potential to develop compromised immune system responses (e.g. HIV-infected patients).